But genes make up only a small slice of our genetic code. Just around 2% of DNA contains our 20,000-odd genes. The other 98% has long been labelled the non-coding genome, or so-called ‘junk’ DNA. This larger portion includes many of the control switches that determine when genes turn on and how strongly they act.

Astrocytes and hidden DNA switches in the brain

Researchers from UNSW Sydney have now pinpointed DNA switches that help regulate astrocytes. Astrocytes are brain cells that support neurons, and they are known to be involved in Alzheimer’s disease.

In research published on December 18 in Nature Neuroscience, a team from UNSW’s School of Biotechnology & Biomolecular Sciences reported that they tested nearly 1000 possible switches in lab-grown human astrocytes. These switches are strings of DNA called enhancers. Enhancers can sit far from the genes they influence, sometimes separated by hundreds of thousands of DNA letters, which makes them difficult to investigate.

Testing nearly 1000 enhancers at once

To tackle that problem, the researchers combined CRISPRi with single-cell RNA sequencing. CRISPRi is a method that can switch off small stretches of DNA without cutting it. Single-cell RNA sequencing measures gene activity in individual cells. Together, the tools let the team examine the effects of nearly 1000 enhancers in a single large-scale test.

“We used CRISPRi to turn off potential enhancers in the astrocytes to see whether it changed gene expression,” says lead author Dr. Nicole Green.

“And if it did, then we knew we’d found a functional enhancer and could then figure out which gene — or genes — it controls. That’s what happened for about 150 of the potential enhancers we tested. And strikingly, a large fraction of these functional enhancers controlled genes implicated in Alzheimer’s disease.”

Cutting the list from 1000 candidates to about 150 confirmed switches greatly reduces the search area in the non-coding genome for genetic clues linked to Alzheimer’s disease.

“These findings suggest that similar studies in other brain cell types are needed to highlight the functional enhancers in the vast space of non-coding DNA”

Why “in-between” DNA matters for many diseases

Professor Irina Voineagu, who oversaw the study, says the results also provide a useful reference for interpreting other genetic research. The team’s findings create a catalogue of DNA regions that can help explain results from studies looking for disease-related genetic changes.

“When researchers look for genetic changes that explain diseases like hypertension, diabetes and also psychiatric and neurodegenerative disorders like Alzheimer’s disease — we often end up with changes not within genes so much, but in-between,” she says.

Her team directly tested those “in-between” stretches in human astrocytes and showed which enhancers truly control key brain genes.

“We’re not talking about therapies yet. But you can’t develop them unless you first understand the wiring diagram. That’s what this gives us — a deeper view into the circuitry of gene control in astrocytes.”

From gene switches to AI prediction models

Running nearly a thousand enhancer tests in the lab took painstaking effort. The researchers say this is the first time a CRISPRi enhancer screen of this size has been carried out in brain cells. Now that the groundwork has been done, the dataset can also be used to train computer models to predict which suspected enhancers are real gene switches, potentially saving years of lab work.

“This dataset can help computational biologists test how good their prediction models are at predicting enhancer function,” says Prof. Voineagu.

She adds that Google’s DeepMind team is already using the dataset to benchmark their recent deep learning model called AlphaGenome.

Potential tools for gene therapy and precision medicine

Because many enhancers are active only in specific cell types, targeting them could offer a way to fine-tune gene expression in astrocytes without changing neurons or other brain cells.

“While this is not close to being used in the clinic yet — and much work remains before these findings could lead to treatments — there is a clear precedent,” Prof. Voineagu says.

“The first gene editing drug approved for a blood disease — sickle cell anemia — targets a cell-type specific enhancer.”

Dr. Green says enhancer research could become an important part of precision medicine.

“This is something we want to look at more deeply: finding out which enhancers we can use to turn genes on or off in a single brain cell type, and in a very controlled way,” she says.

“Performing Children’s Colorado’s first-ever heart and liver dual organ transplant is an amazing accomplishment for our Pediatric Transplant Program,” said Dr. Megan Adams, surgical director of the Pediatric Liver Transplant and Kidney Transplant Programs. “Thanks to years of dedication and a team committed to being the trusted leaders in pediatric transplant across our seven-state region, we’re grateful to provide this level of care to even more kids who need complex organ transplants to treat life-threatening illnesses and help them live healthy and happy lives.”

Years of Preparation Lead to a Life-Saving Moment

Care teams at Children’s Colorado had spent years preparing for the possibility of a dual heart and liver transplant. Close coordination among specialists in surgery, cardiology, hepatology, and other fields, along with strong backing from hospital leadership, ensured the team was ready when 11-year-old Gracie Greenlaw and her family needed help.

Gracie was born with hypoplastic left heart syndrome (HLHS), a condition in which her heart developed with only one functioning pumping chamber. Before turning three, she underwent three major surgeries, the Norwood, the Glenn and the Fontan, to allow her heart to circulate blood effectively. Although many children with HLHS now survive into adulthood, the condition and its treatments can lead to serious long-term complications, including liver damage and liver failure.

Managing the Long-Term Effects of Congenital Heart Disease

To address these ongoing challenges, Children’s Colorado established the Fontan Multidisciplinary Clinic in 2016 as part of its Single Ventricle Program. The clinic focuses on caring for patients with HLHS and other single ventricle conditions, such as tricuspid atresia and unbalanced common atrioventricular canal, by providing coordinated, whole-patient care.

Through this program, Gracie received continuous monitoring and treatment for both her heart and liver. Her care team included experts like cardiologist Dr. Kathleen Simpson and hepatologist Dr. Dania Brigham, who worked together to manage her condition until a transplant became the best option.

“The Fontan is a lifesaving surgery, but the longer someone lives after the procedure, there is an increased chance of developing comorbidities,” Simpson said. “Our care team worked to keep her healthy and living a typical day-to-day life as long as possible before we determined a dual organ transplant would give her the best long-term quality of life.”

Preparing for a Complex Dual Organ Transplant

For years, Gracie lived with plastic bronchitis, a condition that causes thick, protein-like material to build up in the airways. Over the past year, her symptoms worsened, and signs of liver failure began to appear. Her medical team concluded that moving forward with a dual transplant was necessary, and she was placed on the transplant waitlist in April.

In preparation, dozens of specialists met regularly to plan for the surgery. They carefully accounted for the challenges of transplanting two organs at once, including differences in blood volume needs and electrolyte management during the operation.

A Carefully Orchestrated 16-Hour Surgery

Less than a month after joining the waitlist, compatible donor organs became available, made possible by another family’s decision to donate. Because the heart can only remain viable for a short time, the surgical team began with the heart transplant. Dr. Matthew Stone, surgical director of the Pediatric Heart Transplant Program, and congenital heart surgeon Dr. Emily Downs led the nine-hour procedure.

While the heart surgery was underway, the donor liver was maintained on a TransMedics Organ Care System — a specialized device designed to replicate normal liver function. This technology preserved the liver and allowed the heart surgeons the time they needed to complete their work. Dr. Adams and transplant surgeon Dr. Kendra Conzen then performed the liver transplant, which took an additional seven hours. Throughout the process, close coordination with anesthesiology teams was essential to protect Gracie’s health.

Recovery and a Return to Everyday Life

The surgery was successful. Gracie left the cardiac progress care unit just over a month later. Seven months after the transplant, she continues to attend monthly follow-up visits, but she has returned to school and is back home with her dogs.

Like other pediatric heart transplant recipients, Gracie will need another heart transplant later in life. Her transplanted liver, however, is expected to last for the rest of her lifetime.

“This procedure showcases the expertise, talent and level of care Children’s Colorado provides to our patients, including those with complex medical needs,” said Dr. Duncan Wilcox, Surgeon in Chief. “As the top-ranked pediatric hospital in Colorado and the Rocky Mountain region, we are proud of our leading-edge transplant care and look forward to supporting more patients who need dual organ transplants in the future.”

A new JNeurosci paper offers insight into this puzzle. Athanasios Alexandris and colleagues at Johns Hopkins University used mice to study what happens inside the visual system after traumatic brain injury. The visual system includes cells in the eye that send information to the brain, allowing animals and humans to see. Damage to this system can disrupt communication between the eye and the brain, leading to vision problems.

Surviving Cells Rebuild Eye to Brain Connections

After injury, the researchers closely tracked the connections between cells in the eye and neurons in the brain. Instead of finding widespread regrowth of new cells, they observed something different. The cells that survived the injury began to adapt.

These surviving cells grew extra branches, which allowed them to connect with more neurons in the brain than before. This process, known as sprouting, helped compensate for cells that were lost due to injury. Over time, the number of connections between the eye and the brain returned to levels similar to those seen before the injury occurred.

Importantly, these rebuilt connections were not just structural. Measurements of brain activity showed that the new pathways were working properly and could transmit signals effectively. In practical terms, this means the visual system was able to function again despite the damage.

Sex Differences in Visual System Recovery

The study also revealed a significant difference between male and female mice. While male mice showed strong recovery through this compensatory sprouting process, female mice experienced slower or incomplete repair. The eye to brain connections in females did not always fully return to preinjury levels.

According to the authors, these findings point to a recovery mechanism that operates differently depending on sex. As Alexandris explains, “We didn’t expect to see sex differences, but this aligns with clinical observations in humans. Women experience more lingering symptoms from concussion or brain injury than men. Understanding the mechanism behind the branch sprouting we observed — and what delays or prevents this mechanism in females — could eventually point toward strategies to promote recovery from traumatic or other forms of neural injury.”

The research team plans to continue investigating why this repair process differs between females and males. By uncovering the biological factors that influence neural recovery, they hope to identify new ways to improve healing after brain injuries, including concussions and other forms of trauma.